Δευτέρα 30 Οκτωβρίου 2017
Extracellular small heat shock proteins: exosomal biogenesis and function
Abstract
Small heat shock proteins (sHsps) belong to the family of heat shock proteins (Hsps): some are induced in response to multiple stressful events to protect the cells while others are constitutively expressed. Until now, it was believed that Hsps, including sHsps, are present inside the cells and perform intracellular functions. Interestingly, several groups recently reported the extracellular presence of Hsps, and sHsps have also been detected in sera/cerebrospinal fluids in various pathological conditions. Secretion into the extracellular milieu during many pathological conditions suggests additional or novel functions of sHsps in addition to their intracellular properties. Extracellular sHsps are implicated in cell-cell communication, activation of immune cells, and promoting anti-inflammatory and anti-platelet responses. Interestingly, exogenous administration of sHsps showed therapeutic effects in multiple disease models implying that extracellular sHsps are beneficial in pathological conditions. sHsps do not possess signal sequence and, hence, are not exported through the classical Endoplasmic reticulum-Golgi complex (ER-Golgi) secretory pathway. Further, export of sHsps is not inhibited by ER-Golgi secretory pathway inhibitors implying the involvement of a nonclassical secretory pathway in sHsp export. In lieu, lysoendosomal and exosomal pathways have been proposed for the export of sHsps. Heat shock protein 27 (Hsp27), αB-crystallin (αBC), and Hsp20 are shown to be exported by exosomes. Exosomes packaged with sHsps have beneficial effects in in vivo disease models. However, secretion mechanisms and therapeutic use of sHsps have not been elucidated in detail. Therefore, this review aimed at highlighting the current understanding of sHsps (Hsp27, αBC, and Hsp20) in the extracellular medium.
Views of Dermatopathologists about Clonality Assays in the Diagnosis of Cutaneous T cell and B cell Lymphoproliferative Disorders
Background
Appropriate use criteria have been developed for many tests using expert judgment, evidence-based practice, and clinical experience. In this context, the opinions of practitioners about clonality assays in various clinical scenarios where cutaneous lymphoma is suspected are reported.
Methods
An Appropriate Use Criteria Task Force sponsored by the American Society of Dermatopathology (ASDP) synthesized clinical scenarios for cutaneous lymphoproliferative disorders (LPD). We conducted, summarized, and presented a relevant literature search to an audience of 144 dermatopathologists with a variety of practice experiences at the 53rd Annual Meeting of the ASDP in Chicago, IL.
Results
27 clinical scenarios for lymphoproliferative disorders (13 T cell and 14 B cell) were defined. 40 relevant studies for T-cell receptor gene clonality assays and 20 relevant studies for IgH/IgK clonality assays were identified. Audience response data from participating dermatopathologists reflected a wide variety of approaches to the application of clonality assays in the evaluation of LPDs, based on practice setting, personal experience and test availability.
Conclusions
Our clinical scenario analysis and literature review revealed well supported clinical scenarios and identified opportunities for additional research to further define the utility of clonality assays in some clinical scenarios.
Soforttypreaktionen auf Protonenpumpeninhibitoren am Beispiel von Pantoprazol und Omeprazol
Zusammenfassung
Protonenpumpeninhibitoren (PPIs) gehören zu den am häufigsten eingenommenen Medikamenten weltweit. Allergien auf diese Substanzgruppe sind selten, können aber zu schweren Soforttypreaktionen führen. Insbesondere treten auch Kreuzreaktionen zwischen den verschiedenen PPIs auf. In dieser Fallserie werden 4 Patienten mit Soforttypreaktionen auf die Protonenpumpenhemmer Pantoprazol und/oder Omeprazol beschrieben.
2017 HIV Medicine Association of Infectious Diseases Society of America Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With Human Immunodeficiency Virus
Abstract
Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Evolving Understanding of the Causes of Pneumonia in Adults, With Special Attention to the Role of Pneumococcus
Abstract
Before 1945, Streptococcus pneumoniae caused more than 90% of cases of pneumonia in adults. After 1950, the proportion of pneumonia caused by pneumococcus began to decline. Pneumococcus has continued to decline; at present, this organism is identified in fewer than fewer10%–15% of cases. This proportion is higher in Europe, a finding likely related to differences in vaccination practices and smoking. Gram-negative bacilli, Staphylococcus aureus, Chlamydia, Mycoplasma, and Legionella are each identified in 2%–5% of patients with pneumonia who require hospitalization. Viruses are found in 25% of patients, up to one-third of these have bacterial coinfection. Recent studies fail to identify a causative organism in more than 50% of cases, which remains the most important challenge to understanding lower respiratory infection. Our findings have important implications for antibiotic stewardship and should be considered as new policies for empiric pneumonia management are developed.Pneumonia Mortality in Children Aged <5 Years in 56 Countries: A Retrospective Analysis of Trends from 1960 to 2012
Abstract
Background
Pneumonia is now the second leading cause of death for children aged <5 years worldwide. However, analyses of the long-term evolution of under-5 mortality from pneumonia are still scarce in the literature. We aimed to explore long-term trends of under-5 mortality from pneumonia in 56 countries from 1960 to 2012. Methods
Data on under-5 mortality from pneumonia were extracted from the World Health Organization mortality database. Long-term trends were assessed for 56 countries and for 4 national income transition groups. We also used joinpoint regression analysis to detect distinct period segments of long-term trends and estimate the annual percent of changes of each period segment. Results
The average mortality rate from pneumonia for children aged 0–4 years in 56 countries declined from 163.0 per 100000 children (95% confidence interval [CI], 119.4 to 212.8) in 1960 to 9.9 per 100000 children (95% CI, 6.4 to 13.4) in 2012, with an average annual percent of change of −5.6% (95% CI, −7.2% to −3.9%). The temporal trends of childhood mortality were different between national income transition groups. Conclusions
Our findings suggest a striking overall downward trend in under-5 mortality from pneumonia between 1960 and 2012. However, the rate and absolute terms of decline differ by national income transition group. These variable patterns between national income transition groups may inform further intervention setting and priority setting.2017 HIVMA of IDSA Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With HIV
Abstract
Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Assessment of Efficacy and Safety of Arterolane Maleate–Piperaquine Phosphate Dispersible Tablets in Comparison With Artemether-Lumefantrine Dispersible Tablets in Pediatric Patients With Acute Uncomplicated Plasmodium falciparum Malaria: A Phase 3, Randomized, Multicenter Trial in India and Africa
Abstract
Background
Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children. Methods
This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days. Results
The cure rate (ie, polymerase chain reaction–corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%–2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, –2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar. Conclusions
The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients. Clinical Trials Registration
CTRI/2014/07/004764.Empiric Therapy With Carbapenem-Sparing Regimens for Bloodstream Infections due to Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae: Results From the INCREMENT Cohort
Abstract
Background
There is little information about the efficacy of active alternative drugs to carbapenems except β-lactam/β-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems. Methods
A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed. Cox regression including a propensity score for receiving OADs was performed to analyze 30-day all-cause mortality as main outcome. Clinical failure and length of stay were also analyzed. Results
Overall, 335 patients were included; 249 received empiric carbapenems and 86 OADs. The most frequent OADs were aminoglycosides (43 patients) and fluoroquinolones (20 patients). Empiric therapy with OADs was not associated with mortality (hazard ratio [HR], 0.75; 95% confidence interval [CI], .38–1.48) in the Cox regression analysis. Propensity score–matched pairs, subgroups, and sensitivity analyses did not show different trends; specifically, the adjusted HR for aminoglycosides was 1.05 (95% CI, .51–2.16). OADs were neither associated with 14-day clinical failure (adjusted odds ratio, 0.62; 95% CI, .29–1.36) nor length of hospital stay. Conclusions
We were unable to show that empiric treatment with OAD was associated with a worse outcome compared with carbapenems. This information allows more options to be considered for empiric therapy, at least for some patients, depending on local susceptibility patterns of ESBL-E.Short-term Peripheral Venous Catheter–Related Bloodstream Infections: A Systematic Review
Abstract
Short-term peripheral venous catheters (PVCs) are commonly used in healthcare settings. To determine the magnitude of bloodstream infections (BSIs) related to their use, PubMed, article bibliographies, and the authors' library were searched for pertinent articles. The incidence of PVC-related BSIs was 0.18% among 85063 PVCs. Short-term PVCs accounted for a mean of 6.3% and 23% of nosocomial BSIs and nosocomial catheter-related BSIs, respectively. Prolonged dwell time and catheter insertion under emergent conditions increased risk of PVC-related bloodstream infection (PVCR-BSI). If approximately 200 million PVCs are successfully inserted into adult patients each year in the United States, there may be many PVCR-BSIs occurring yearly. Clinicians should obtain blood cultures in patients with evidence of PVC infection and systemic symptomatology such as fever, carefully inspect the PVC insertion site in bacteremic or fungemic patients, and remove PVCs associated with localized infection with or without associated BSI.Treatment of Early Syphilis
To the Editor—Andrade and colleagues addressed an important clinical issue in their randomized study of 1 vs 3 penicillin injections for human immunodeficiency virus (HIV)–infected patients with early syphilis [1]. However, there remain several questions. First, the estimated difference in treatment success between the 2 arms was substantial (95% vs 75%), resulting in the calculation of a moderate sample size of 108 patients for the study. However, the literature does not give any evidence that 20% of differences in the outcome have to be expected between the enhanced vs standard group [2]. Nevertheless, the authors were not able to fully enroll the study and finally closed on only 64 patients. The allocation of patients to the 2 study arms was not sufficiently balanced. Fifty-five percent were treated with 1 penicillin injection and 45% with 3 penicillin injections. Furthermore, the geometric means of the rapid plasma reagin (RPR) titers at baseline were not well balanced (116 vs 78, respectively). Both the sample size calculations and the imbalances in study patients severely impact the clinical significance of the study. Moreover, the response rates after 12 months differed substantially between groups (80% vs 93%). As the conception for the trial was not a noninferiority study, the results do not allow the conclusion that 1 injection of penicillin is not inferior to 3 injections. Taken together, we cannot agree with the authors' conclusion that a larger study would only detect a small but clinically insignificant difference in treatment outcome.
Redefining Human Immunodeficiency Virus (HIV) Preexposure Prophylaxis Failures
To the Editor—Failures of daily oral human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine are rare, with only 3 HIV seroconversions documented among patients adherent to PrEP at the time of infection [1–3]. However, PrEP failures could be defined more broadly as HIV infections that occur at any point along the PrEP continuum of care [4]. Here, we describe HIV infections among individuals who sought or were referred for PrEP within the Kaiser Permanente Northern California (KPNC) healthcare system.
Uptake of Antibiotic Stewardship Programs in US Acute Care Hospitals: Findings From the 2015 National Healthcare Safety Network Annual Hospital Survey
Abstract
To assess uptake of the Centers for Disease Control and Prevention's Core Elements of Hospital Antibiotic Stewardship Programs, we analyzed stewardship practices as reported in the 2015 National Healthcare Safety Network's Annual Hospital Survey. Hospital uptake of all 7 core elements increased from 40.9% in 2014 to 48.1% in 2015.Successful Therapy of a Multidrug-Resistant Extended-Spectrum β-Lactamase–Producing and Fluoroquinolone-Resistant Salmonella enterica Subspecies enterica Serovar Typhi Infection Using Combination Therapy of Meropenem and Fosfomycin
Abstract
We report a traveler who acquired a Salmonella enterica subspecies enterica serovar Typhi strain with resistance against β-lactams, cephalosporins (extended-spectrum β-lactamase–producing type SHV-12), and quinolones (plasmid-mediated quinolone resistance gene qnrB7). After clinical deterioration using meropenem monotherapy, treatment success was achieved after commencement of fosfomycin in conjunction with high-dose meropenem. The case illustrates clinical challenges of multidrug-resistant S. Typhi.
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